6-32167373-C-T

Variant names:

• chr6-32167373-C-T
• rs759709000
• NM_030652.4:c.625C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030652.4(EGFL8):​c.625C>T​(p.Arg209Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,460,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: EGFL8 NM_030652.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0330

Genes affected

EGFL8 (HGNC:13944): (EGF like domain multiple 8) Predicted to enable signaling receptor binding activity. Predicted to be involved in anatomical structure development. Predicted to act upstream of or within in utero embryonic development. Predicted to be active in cell surface and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

PPT2-EGFL8 (HGNC:48343): (PPT2-EGFL8 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring PPT2 (palmitoyl-protein thioesterase 2) and EGFL8 (EGF-like-domain, multiple 8) genes located in the major histocompatibility complex class III region of chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21684948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFL8	NM_030652.4	c.625C>T	p.Arg209Cys	missense_variant	Exon 7 of 9	ENST00000333845.11	NP_085155.1
EGFL8	NR_037860.2	n.740C>T		non_coding_transcript_exon_variant	Exon 7 of 9
PPT2-EGFL8	NR_037861.1	n.2142C>T		non_coding_transcript_exon_variant	Exon 14 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFL8	ENST00000333845.11	c.625C>T	p.Arg209Cys	missense_variant	Exon 7 of 9	1	NM_030652.4	ENSP00000333380.6
PPT2-EGFL8	ENST00000422437.5	n.*541C>T		non_coding_transcript_exon_variant	Exon 15 of 21	5		ENSP00000457534.1
PPT2-EGFL8	ENST00000422437.5	n.*541C>T		3_prime_UTR_variant	Exon 15 of 21	5		ENSP00000457534.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245506 Hom.: 0 AF XY: 0.00000747 AC XY: 1 AN XY: 133928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000911

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460672 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 726648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000848 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.625C>T (p.R209C) alteration is located in exon 7 (coding exon 6) of the EGFL8 gene. This alteration results from a C to T substitution at nucleotide position 625, causing the arginine (R) at amino acid position 209 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.74	.;T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L;L;.
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.92	P;P;.
Vest4		0.23
MutPred		0.48		Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);.;
MVP		0.93
MPC		0.58
ClinPred		0.18	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759709000; hg19: chr6-32135150;